RESUMO
BACKGROUND: Cardiac contractile function requires high energy from mitochondria, and Ca2+ from the sarcoplasmic reticulum (SR). Via local Ca2+ transfer at close mitochondria-SR contacts, cardiac excitation feedforward regulates mitochondrial ATP production to match surges in demand (excitation-bioenergetics coupling). However, pathological stresses may cause mitochondrial Ca2+ overload, excessive reactive oxygen species production and permeability transition, risking homeostatic collapse and myocyte loss. Excitation-bioenergetics coupling involves mitochondria-SR tethers but the role of tethering in cardiac physiology/pathology is debated. Endogenous tether proteins are multifunctional; therefore, nonselective targets to scrutinize interorganelle linkage. Here, we assessed the physiological/pathological relevance of selective chronic enhancement of cardiac mitochondria-SR tethering. METHODS: We introduced to mice a cardiac muscle-specific engineered tether (linker) transgene with a fluorescent protein core and deployed 2D/3D electron microscopy, biochemical approaches, fluorescence imaging, in vivo and ex vivo cardiac performance monitoring and stress challenges to characterize the linker phenotype. RESULTS: Expressed in the mature cardiomyocytes, the linker expanded and tightened individual mitochondria-junctional SR contacts; but also evoked a marked remodeling with large dense mitochondrial clusters that excluded dyads. Yet, excitation-bioenergetics coupling remained well-preserved, likely due to more longitudinal mitochondria-dyad contacts and nanotunnelling between mitochondria exposed to junctional SR and those sealed away from junctional SR. Remarkably, the linker decreased female vulnerability to acute massive ß-adrenergic stress. It also reduced myocyte death and mitochondrial calcium-overload-associated myocardial impairment in ex vivo ischemia/reperfusion injury. CONCLUSIONS: We propose that mitochondria-SR/endoplasmic reticulum contacts operate at a structural optimum. Although acute changes in tethering may cause dysfunction, upon chronic enhancement of contacts from early life, adaptive remodeling of the organelles shifts the system to a new, stable structural optimum. This remodeling balances the individually enhanced mitochondrion-junctional SR crosstalk and excitation-bioenergetics coupling, by increasing the connected mitochondrial pool and, presumably, Ca2+/reactive oxygen species capacity, which then improves the resilience to stresses associated with dysregulated hyperactive Ca2+ signaling.
Assuntos
Sinalização do Cálcio , Retículo Sarcoplasmático , Feminino , Camundongos , Animais , Retículo Sarcoplasmático/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Mitocôndrias Cardíacas/metabolismo , Cálcio/metabolismoRESUMO
Metabolic diseases (MetDs) embrace a series of pathologies characterized by abnormal body glucose usage. The known diseases included in this group are metabolic syndrome, prediabetes and diabetes mellitus types 1 and 2. All of them are chronic pathologies that present metabolic disturbances and are classified as multi-organ diseases. Cardiomyopathy has been extensively described in diabetic patients without overt macrovascular complications. The heart is severely damaged during the progression of the disease; in fact, diabetic cardiomyopathies are the main cause of death in MetDs. Insulin resistance, hyperglycaemia and increased free fatty acid metabolism promote cardiac damage through mitochondria. These organelles supply most of the energy that the heart needs to beat and to control essential cellular functions, including Ca2+ signalling modulation, reactive oxygen species production and apoptotic cell death regulation. Several aspects of common mitochondrial functions have been described as being altered in diabetic cardiomyopathies, including impaired energy metabolism, compromised mitochondrial dynamics, deficiencies in Ca2+ handling, increases in reactive oxygen species production, and a higher probability of mitochondrial permeability transition pore opening. Therefore, the mitochondrial role in MetD-mediated heart dysfunction has been studied extensively to identify potential therapeutic targets for improving cardiac performance. Herein we review the cardiac pathology in metabolic syndrome, prediabetes and diabetes mellitus, focusing on the role of mitochondrial dysfunctions.
Assuntos
Cardiomiopatias Diabéticas , Resistência à Insulina , Cardiomiopatias Diabéticas/metabolismo , Metabolismo Energético , Humanos , Mitocôndrias/metabolismo , Mitocôndrias Cardíacas/metabolismo , Dinâmica MitocondrialRESUMO
OBJECTIVE: To report our experience with the management of twin pregnancies discordant for lower urinary tract obstruction. METHODS: Cases of twin pregnancies discordant for lower urinary tract obstruction were identified from our fetal medicine database. Information on ultrasonographic findings, antenatal course, pregnancy complications, and perinatal outcome was obtained by reviewing medical records or contacting the referring obstetricians. RESULTS: Five twin pregnancies discordant for lower urinary tract obstruction were diagnosed between 11 and 15 weeks of gestation. There were 3 dichorionic and 2 monochorionic pregnancies (1 diamniotic and 1 monoamniotic). The dichorionic pregnancies were managed conservatively, resulting in a pregnancy loss of both twins in 1 case, a single fetal death at 29 weeks in 1 case, and an early neonatal death due to lung hypoplasia of the affected twin in 1 case. On the other hand, both monochorionic twin pregnancies were managed with serial vesicocenteses. In both cases, the prenatal course was complicated, 1 by premature rupture of the membranes and the other by cord entanglement, requiring delivery at 29 and 31 weeks, respectively. Among the 4 continuing pregnancies with complete perinatal outcome, none of the affected twins survived, and the structurally normal twins were delivered between 29 and 36 weeks and discharged from the hospital in good condition. CONCLUSION: Twin pregnancies discordant for lower urinary tract obstruction are at high risk of perinatal death and premature delivery. Prenatal intervention seems not to be associated with an improved perinatal outcome of the affected twin, but it may be beneficial in selected cases to attain viability of the unaffected twin.
Assuntos
Doenças em Gêmeos/diagnóstico , Doenças em Gêmeos/terapia , Doenças Fetais/diagnóstico , Doenças Fetais/terapia , Obstrução Uretral/diagnóstico , Obstrução Uretral/terapia , Doenças em Gêmeos/congênito , Feminino , Idade Gestacional , Humanos , Gravidez , Resultado da Gravidez , Estudos Retrospectivos , Resultado do Tratamento , Ultrassonografia Pré-Natal , Obstrução Uretral/congênitoRESUMO
Se presentan 14 pacientes con presunta toxocariasis ocular. El diagnóstico se basó en hallazgos fundoscópicos y un ELISA test mayor o igual a 1:8. Las manifestaciones clínicas más frecuentes fueron una masa inflamatoria periférica, granuloma de polo posterior y endoftalmitis. Presentaciones raras fueron granuloma del disco óptico y neurorretinitis y vitreítis difusa. Los esteroides fueron efectivos para combatir el proceso inflamatorio en la etapa aguda. La enfermedad condujo a una ceguera en 64,3% de los casos, a pesar del tratamiento. Se enfatiza la importancia de la prevención primaria